The main goal of this competitive renewal application is to investigate the appropriateness and the relative site- specific clinical potential of a range of image-guided IMRT (IG-IMRT) strategies for taking into account inter-fractional changes in anatomy. Our hypothesis is that the application of appropriate IG-IMRT strategies of varying sophistication and complexity will lead to more conformal tailoring and to higher accuracy of delivered dose distributions, allowing significant reduction of normal tissues exposed to damaging levels of radiation doses or escalation of tumor doses, or both. There are many possible IG-IMRT strategies, including some that are highly advanced and complex ones that involve daily CT-image-guided setup and online near real-time replanning. The appropriateness of each strategy for a given site-specific clinical situation will be determined as a part of this research proposal and will depend upon the magnitude and the nature of the inter-fractional anatomic variations, the treatment technique (e.g., stereotactic, hypo-fractionated) and cost vs. clinical benefit considerations. To test our hypothesis, we will (1) adapt, optimize, develop, where necessary, and evaluate the effectiveness of image segmentation and deformable registration methods; (2) develop and evaluate methods and software for designing and delivering IMRT specifically for different offline and online adaptive and corrective IG-IMRT strategies; and (3) conduct preclinical treatment design studies to assess the merits of alternate IG-IMRT strategies relative to current practices as well as to each other by applying them to cases of prostate, head-and-neck and video-feedback-guided gated or breath-hold lung treatments. The clinical rationale for the proposed research is that its results will, in the long run, lead to significant improvements in outcome in terms of lower normal tissue toxicity, higher local control, or both. In addition, the accurate knowledge of the dose distributions actually delivered will improve the quality of dose-response data. To accomplish our goal, we intend to leverage the advances we made through our IMRT research in the previous two funding cycles.